There are too many plausible permutations and scale-up scenarios of combination hepatitis C (HCV) interventions for exhaustive testing in experimental trials. Therefore, we used computer simulation to project the health and economic impact of alternative combination intervention scenarios for people who inject drugs (PWID), focusing on direct anti-viral agents (DAA) and medication-assisted treatment combined with syringe access programs (MAT+).We performed an allocative efficiency study using a mathematical model simulating the progression of HCV in PWID and its related consequences. Two previously validated simulations were combined to estimate the cost-effectiveness of intervention strategies that included a range of coverage levels. Analyses were performed from a health sector and societal perspective with a 15-year time horizon and a discount rate of 3%.From a health-sector perspective (excluding criminal justice system-related costs), four potential strategies fell on the cost-efficiency frontier. DAA at 20% coverage had an ICER of $27,251/QALY. Combinations of DAA 20% with MAT+ at 20%, 40%, and 80% coverage had ICERs of $165,985/QALY, $325,860/QALY, and $399,189/QALY, respectively. When analyzed from a societal perspective (including criminal justice system-related costs), DAA 20% with MAT+ 80% was most effective and was cost saving. While DAA 20% with MAT+ 80% was more expensive (e.g., less cost-saving) than MAT+ 80% alone without DAA, it offered favorable value compared to MAT+ 80% alone ($23,932/QALY).When considering health sector costs alone, DAA alone was the most cost-effective intervention. However, with criminal justice system-related costs, DAA and MAT+ implemented together become the most cost-effective interventions.